EFFICACY OF PUVA THERAPY IN VARIOUS TYPES OF...

EFFICACY OF PUVA THERAPY IN VARIOUS

TYPES OF VITILIGO

Dissertation Submitted to

THE TAMIL NADU DR. M.G.R. MEDICAL UNIVERSITY

in partial fulfillment of the regulations

for the award of the degree of

M.D. (Dermatology, Venereology and Leprology) BRANCH – XII

GOVT. STANLEY MEDICAL COLLEGE & HOSPITAL THE TAMIL NADU DR. M.G.R. MEDICAL UNIVERSITY

CHENNAI, INDIA.

MARCH 2007

CERTIFICATE

This is to certify that the dissertation entitled “EFFICACY OF PUVA

THERAPY IN VARIOUS TYPES OF VITILIGO” is the bonafide original

work of Dr. K. MEENAKSHI, in partial fulfillment of the requirements for M.D.

(Dermatology, Venereology and Leprology) BRANCH – XII Examination of the

Tamilnadu Dr. M.G.R. Medical University to be held in March 2007. The period of

study was from February 2005 to March 2006.

Dr. D.R. GUNASEKARAN, M.S. DEAN

Govt. Stanley Medical College & Hospital,

Chennai-600 001.

Dr. A.M. JAYARAAMAN, M.D., D.D. Professor & Head

Department of Dermatology Govt. Stanley Medical College

Chennai-600 001.

DECLARATION

I, Dr. K. MEENAKSHI, solemnly declare that dissertation

titled, “EFFICACY OF PUVA THERAPY IN VARIOUS TYPES OF

VITILIGO” is a bonafide work done by me at Govt. Stanley Medical College

& Hospital during 2004-2007 under the guidance and supervision of

Dr. A.M. JAYARAAMAN, M.D., D.D., Professor and Head, Department of

Dermatology, Stanley Medical College, Chennai-600 001.

The dissertation is submitted to Tamilnadu, Dr. M.G.R. Medical

University, towards partial fulfillment of requirement for the award of

M.D. Degree (BRANCH – XII ) in Dermatology, Venereology and

Leprology.

Place : Chennai.

Date :

(Dr. K. MEENAKSHI)

ACKNOWLEDGEMENT

The trend in medical care is toward personalized and predictive

therapeutics. Individual variation in responsiveness and toxicity is increasingly

recognized. We are on the edge of a revolution in health care.

We expect that many of the new treatments will be increasingly used in

a cost effective manner. The arrival of photochemotherapy had revolutionized

the treatment for vitiligo.

I thank Dr. D.R. GUNASEKARAN, M.S., FICS., Dean, Govt. Stanley

Hospital for permitting me to conduct the study.

First and foremost, I am ever thankful to my Professor of Dermatology,

Dr. A.M. JAYARAAMAN, M.D., D.D., who has always an eye for new

methods of treatments for all dermatological conditions, for offering me this

unique opportunity of conducting the study of “The efficacy of 8 MOP –

PUVA therapy for vitiligo patients” – He offered me a series of management of

approaches in a simple and understandable manner which were of great

inspiration and enthusiasm for me to conduct this study with extreme interest

and sincerity. He was the main guiding force behind me and without whose

periodical advices and updating the data, I could not have completed this

dissertation into its complete shape.

I am grateful to Dr. KIRUBHA MOHAN, M.D., D.D., Additional

Professor, Department of Dermatology and the team of Assistant Professors

who showed no restraint in sparing time to review my articles inspite of their

daily hectic academic and personal activities. So also they have given me

valuable assistances in many ways like for eg. by providing the references

pertaining to the treatment of vitiligo by PUVA therapy. These were really of

much use in periodically evaluating the progress of the improvements and

comparing my results with those of many others from around the world. I

request them to accept the collective acknowledgement of my appreciation.

Derma India’s Technical Staff were Kind enough in periodically

checking the PUVA instruments used by me through this department

throughout this study. I am grateful to them all for their co-operation, technical

skill, fast and quick action whenever I encountered faults in the PUVA

instruments.

I am very thankful to the hospital statistician for his help in

reassembling all my data and providing me with an understandable and correct

tables in short notice.

My thanks are always due to the unforgettable, very co-operative and

understanding patients who never failed to turn up on the dates given to them

for the PUVA therapy without whose undeniable support and co-ordination,

this study could not have come to a complete shape.

In conclusion, on behalf of me I wish to place on record my

indebtedness and gratitude to all contributors from this institution and outside.

CONTENTS

Serial. No.

Title Page No.

1. INTRODUCTION 1

2. AIM 5

3. REVIEW OF LITERATURE 6

4. MATERIALS AND METHODS 46

5. METHODOLOGY 48

6. RESULTS 51

7. DISCUSSION 56

8. CONCLUSION 62

9. BIBLIOGRAPHY

10. ANNEXURE

Proforma

Master chart.

1

INTRODUCTION

Vitiligo is an acquired common pigmentary disorder clinically

characterized by the development of depigmented macules which are

caused by the destruction of melanocytes in the affected areas . This is

described in the Hindu sacred book ATTARVA VEDA in 1400 B.C.

This had been often confused with leprosy .This misconception among

the people is the basis for the social stigma tagged with this disease. In

certain culture, patients with vitiligo are still regarded as social outcasts.

About 0.5 – 1 % of general population suffer from vitiligo. Half

of all the patients develop the disease before the age of twenty. Onset at

an old age occurs but is unusual and should raise concern about

underlying disorders or associated diseases52.

Generalized vitiligo is the most common clinical presentation and

commonly involves the face and acral area. Vitiligo is not a life

threatening disease and does not require treatment unless severe

cosmetic disfigurement causes emotional and social distress9.

Most often, depigmentation is gradually progressive process but

in generalized vitiligo , patients may report a sudden onset with rapid

spread of vitiligo over a period of few months . Subsequently the disease

2

may remain quiescent for many years. Upto thirty percent of the patients

report “spontaneous” repigmentation, which appears in perifollicular

and marginal areas of sun exposed lesions during the summer months.

Complete sunlight induced repigmentation is extremely rare.

Independently of the initial course of the disease, vitiligo may come to a

halt and remain stable for decades. Focal and segmental vitiligo usually

do not extend beyond their initial regional distribution, and once the

expansion stops, they tend to be quite stable .Segmental vitiligo can also

occur as a distinctive part of generalized disease and may precede its

onset10. At present there is no universally effective drug for vitiligo

therapy. The various treatment modalities include steroids (topical and

systemic), cyclophosphamide pulse, and clofazamine , placentrex

(topical and injection) , autologous melanocyte transplant, choloroquine,

Khellin – UVA(KUVA), PAUVA (Lphenylalanine + UVA),

fluorouracil (topical), tacrolimus induce temporary clearance with

recurrence after variable intervals14,41.

Of several therapeutic options available one of the promising

therapies is PUVA (Psoralen and UVA). This is based on the

observation that in many patients sun exposed lesions tend to show

follicular repigmentation during the summer months.

3

With the increased sensitivity of vitiligo to sun burn and the

unpredictable dosimetry with natural sunlight, solar phototherapy as not

evolved into a true therapeutic option. On the other hand, first

description of vitiligo treatment with what can be considered photo

chemotherapy dated back about 4000 years which makes PUVA one of

the oldest therapeutic principles that are still in use in the 21st century.

Heliotherapy (sunlight therapy) was first introduced by

Herodotus; a renowned Greek physician of the 2nd century B.C has been

called the Father of Heliotherapy7.

Indians used the tropical plant extract (Psoralea corylifolia)

combined with subsequent sun exposure as early as 1400 B.C. Later

around 12th century A.D., the Egyptians used Psoralen obtained from

another plant Ammi majus7.

Photo chemotherapy of vitiligo was revived for modern medicine

of a century ago when El Mofty published the success of his therapeutic

trial and subsequently identified the Psoralen as the active compound.

Kelly and Pinkus reported some success in treating vitiligo with

oral administration of 8-MOP followed by sunlight exposure. Since

natural sunlight lacks predictability often changing emission spectrum,

4

changing its output as day progresses, in 1960 it was realized that

8-MOP optimally sensitizes the vitiliginous skin at 360 nm., the UV

light box was born7.

In 1974 Parrish et al successfully treated generalized Psoriasis

with oral 8-MOP and high intensity UVA therapy and coined the term

(acronym), PUVA8.

5

AIM

1) To evaluate the efficacy of therapeutic effect of oral psoralen

followed by Ultraviolet - A irradiation (PUVA) for chronic vitiligo

patients who failed to respond to other modalities of treatment for

vitiligo

2) To assess the efficacy of PUVA response at various sites involved.

3) To study the Age, Sex, Family History, Koebnerization, surface

area of involvement and their influence on the PUVA response.

4) To study the association between blood group and its efficacy on

PUVA therapy.

5) To assess the complication due to PUVA therapy.

6

REVIEW OF LITERATURE

HISTORICAL ASPECTS

The word vitiligo might have evolved from the Latin word

“vitium” meaning a defect / blemish. Vitelius signifying a calf’s white

patches. Documentation of the use of the word vitiligo occurred in the

first century A.D. by the Roman physician ‘Celus’.

Indian literature dating to 1500 to 1000 B.C. refers to the word

“kilas” (‘kil’ means white, ‘as’ means to caste) .Palita (‘pal’ implies

grey, old and aged) referring to white patches on the skin. In the sacred

book of Buddhism ‘Vinay Pitak’ (621-544 B.C ) , persons suffering

from kilas were unable to be ordained63.

EPIDEMIOLOGY

Vitiligo occurs all over the world and in all races, it accounts for

about 0.5 –1% of general population59. In India the incidence is as high

as 8.8%3. Family history is noticed in 20-30% of cases59. Inheritance is

thought to be polygenic or autosomal dominant with incomplete

penetrance and variable expression59. It is more in monozygotic twins

than in dizygotic twins. Incidence in Caucasians is 1%. Both sexes are

7

equally affected. Vitiligo may develop at any age and onset has been

reported from birth to 81 years of age. The peak age of onset is between

10 –30 years. Half of them manifest before 20 years28. Segmental

vitiligo appears notably familial53. HLA DR A1 , 0302 , HLA DQ A1,

0601, DQ B1 ,0803 , DR B1-0503 alleles predispose individuals to

vitiligo and HLA DR A1 6501 alleles protect individuals from vitiligo60.

HLA B13 is associated with vitiligo and antithyroid antibodies62.

AETIOLOGY

The exact aetiology is unknown. So various theories are proposed

namely,

1. Autoimmune theory.

2. Neural hypothesis.

3. Self destruction hypothesis.

4. Other prevailing hypothesis.

AUTOIMMUNE THEORY

In vitiligo autoantibodies are directed against various melanocytic

proteins including tyrosinase related proteins 1, 2 which correlate with

8

the disease activity. In progressive vitiligo increased levels of CLA,

active CD8 + T cell in the peripheral blood of the patient28.

Several autoimmune diseases have been associated with vitiligo

such as Hypothyroidism16, Hashimoto’s thyroiditis (20-30%)44,

pernicious anaemia52 (4-20%), Addisons disease37 hypogonadism44,

halonaevus, scleroderma, lichen planus, DLE, rheumatoid arthritis,

alopecia areata3.

Vitiligo is more often associated with late onset diabetes

mellitus56. Diabetes mellitus both juvenile onset and adult onset types

occurs in 1- 7.1% of vitiligo patients and conversely vitiligo occurs in

4.8% of diabetic patients28.

Autoimmune poly endocrinopathy, candidiasis, ectodermal

dystrophy (APECED) with gene mutation in AIRE (autoimmune

regulator) has been increasingly associated with vitiligo52. The presence

of an auto immune reaction of uveal tract along with the meningeal,

cochlear epidermal melanin in Vogt-Koyanaki-Harada Syndrome

leading to destruction of melanin support the role of immune response in

vitiligo49.

9

A non-cytotoxic antikeratinocyte intracellular bodies directed

against 40 KD or 75 KD common tissue antigens and 65 KD and 90 KD

pigment cell specific antigens correlate with the disease activity and

more pronounced in active rather than stable vitiligo63.

In Neural Hypothesis, increased immune reactivity of

neuropeptide Y/ altered balance of nerve growth factor receptors lead to

increased expression of catechol –o-ethyl transferase and mono amino

oxidase and Beta 2 adreno receptors28.

Studies has shown that disturbance of the autonomous nervous

system leading to depigmentation may lead to vaso constriction.

1. Clinical evidence of segmental and dermatomal vitiligo.

2. Increased sweating and vaso constriction in vitiliginous areas

implies increased adrenergic activity.

3. Elevated levels of tumour necrosis factor α (TNFα), intercellular

adhesion molecule –1 (ICAM 1) and Interferon γ have been

found in perilesional skin in the vitiligo patients64.

Degenerative and regenerative changes were found in the

terminal regions of the small proportion of the nerve supplying central

10

and marginal regions of vitiliginous lesions indicating that affected

nerves were auto immune in function6.

SELF DESTRUCTION HYPOTHESIS:

A.B. Lerner states that loss of intrinsic protective mechanism that

eliminate toxic intermediate metabolite in the melanocytic pathways

leads to the accumulation of 5,6,7,8, tetrahydrobiopterin which increase

the production of hydrogen peroxide28.

OTHER PREVAILING HYPOTHESIS:

1) Intrinsic defect of structure and function of rough endoplasmic

reticulum in vitiligo melanocytes.

2) Deficiency in melanocyte growth factor.

3) Dysregulation of melanocyte apoptosis.

4) Primary disturbance in T cell resulting in the development of

forbidden clones of auto reactive lymphocytes in the epidermis28.

In Vitiligo, onset of the activity often attributes to emotional

stress which causes increased release of catecholamines from nerve

endings19.

11

Studies have shown that reduced zinc level significantly

correlates with vitiligenous lesion61.

Lower level of catalase and UV induced damage to the epidermis

release free reactive oxygen species which are cytotoxic to melanocytes

and also inhibit tyrosinase32.

Emotional factors, physical injury, sunburn are often associated

with the onset of the disease19.

Spontaneous repigmentation was due to the release of cytokine

from the donor site when stimulating the vitiliginous patch and hair

follicle of the grafted site65.

CLASSIFICATION OF VITILIGO (after Fitzpatrick 1987)58,29:

VITILIGO

Localised Generalised Mixed

Focal Segmental Acrofacial

Vitiligo Vulgaris

Universal Vitiligo

12

1. LOCALISED:

Focal –one or more patches, non dermatomal distribution

Segmental –one or more patches in dermatomal distribution.

2. GENERALISED

a. Acrofacial – Acral (hands and feet)

Orificial (around mouth and genitals, eyes, nose and ears)

Lip tip (Acral, nipple, genital, lips)

b. Vulgaris - Scattered patches in symmetrical or asymmetrical

distribution

c. Universal - Total or near total.

2. Mixed -

Segmental with acro-orificial or vulgaris

Trichrome vitiligo –

Uniform, narrow, hypopigmented zone between normally

pigmented skin and the typical vitiligo macules 51.

13

A trichrome lesion naturally evolves to a typical white vitiligo

macule or macules albeit not at a predictable rate. Trichrome vitiligo

occurred mostly on the trunk in active vitiligo vulgaris28. Focal vacuolar

degeneration of the basal cell layer and mild inflammatory cell infiltrate

of epidermis and dermis were prominent in the light brown skin and

perilesional normal skin than in other normal area of the skin. Decreased

number of melanocytes in the tanned skin compared with vitiliginous

skin is observed24.

1. Quadrichrome Vitiligo :

It refers to the fourth colour. This is a marginal hyper-

pigmentation in addition to trichrome vitiligo.

2. Pentachrome Vitiligo :

It has white, tan, brown hyperpigmented, blue grey hyper-

pigmented and normal colour.

3. Blur Vitiligo :

This corresponds to vitiligo macules occurring in the sites of post

inflammatory hyper melanosis.

14

4. Inflammatory Vitiligo :

This has an erythematous raised border similar to that seen in tine

a versicolor.

5. Confetti Macules :

This is seen as multiple vitiliginous macules of 1-2 mm

diameter28.

PSORALEN PHOTO-CHEMOTHERAPY

Psoralen photo – chemotherapy is by which psoralen and UVA

are used to bring beneficial responses to patients suffering form vitiligo.

Such beneficial responses are not produced by the drug or radiation

alone2.

HISTORICAL BACKGROUND

Psoralen and its derivatives are naturally occurring tricyclic furo

coumarins found in more than thirty plants such as lime, lemon,

bergamot, fig cloves, and babache2.

The ancient Egyptians and Indians used plant extracts and applied

to the skin or administered orally in combination with sunlight to

15

produce photo toxicity in vitiliginous skin with subsequent

repigmentation in 1400 B.C7.

The most widely used plant derivatives in photo – chemotherapy

are 8-MOP produced by the plant Ammmi Majus, Ficus carica. 5 MOP

is also known as Bergapten, majudin and Heraclin. This is also produced

by citrus and psoralea corylifolia. These psoralen are present in the

leaves, fruits, seeds, roots, and the rhizome of the plants3.

In 1940 – Isolation of psoralen from Ammi Majus was done7.

In 1947 – El Mofti et al showed the psoralen’s therapeutic

efficacy in vitiligo2.

In 1950- Both topical and oral psoralen was used in vitiligo7.

In 1954- a Pharmacologic study of psoralen by Pathak and

Fitzpatrick in the Unites States and by Musajo and his collaborators in

Italy was done18.

In 1960- Synthetic furo coumarin trimethyl psoralen was used in

the treatment of vitiligo18.

In 1974- Artificial UVA after oral administration of 8 MOP in

psoriasis was called acronym PUVA by Parrish et al2.

16

In 1988 – NUVB was discovered by Van Waden et al and Green

et.al.

In 1997 – Westerhof and Nieweborers first used NBUVBin

Vitiligo66.

TYPES OF PSORALEN AVAILABLE ARE:

1) Natural – 8 Methoxy psoralen (8 MOP)

5 Methoxy psoralen (5 MOP)3.

2) Synthetic – 4,5,8, Trimethyl psoralen

3 carbethoxy psoralen (3 CP)21

8 Methoxy Psoralen (8MOP)

It has molecular weight of 216 .2 and occurs as a white to cream

coloured, odourless solid that forms needle like crystals. It is soluble in

acetone, acetic acid, propylene glycol and benzene. It is sensitive to air

and light and is easily hydrolysed. Its melting point is 148 ° C.

Psoralens are lipophilic, non ionized compounds, very poorly soluble in

water and ether20.

This poor solubility impedes their absorption from the stomach

and the intestine. A micronized crystal in gelatin capsules is more

rapidly and completely absorbed. Fasting condition increase psoralen

absorption. Fatty meal decreases its absorption and delays its peak level.

17

Medication should be taken with water only. Ideally food should be

avoided until after the treatment70.

High level of psoralen in blood under fasting condition can cause

nausea which can be alleviated by taking along with food or milk18.

After absorption psoralen exhibits peak serum level between 1

and 6 hours2. It also exhibits strong but saturable first pass effect

through the intestines and the liver70. 75-85% of methoxalen is

reversible, bound to serum albumin and 98-99% in case of 5 MOP (5

Methoxypsoralen) Epidermal cell binding is about 90% in case of 8 -

MOP, 79% in case of 5- MOP studies have shows that psoralen spreads

rapidly to most organs but binding seems to be short lived and

reversible, provided that there is no exposure to UVA irradiation70.

8-MOP is completely metabolized in the liver and oral 8-MOPhas

serum half life approximately 1 hr and it is rapidly eliminated. There

appears to be no accumulation of metabolites. Hence repeated dose does

not cause significant accumulation of the drug in the body. After

ingestion of psoralen, the skin is most sensitive to UVA after 1-3 hours

but remain active upto 8-12 hours2.

18

The drug is completely excreted in 12hours (80% in 6-8 hours

and 90% in 12hours)2

The unpredictable pharmaco kinetic behaviour is probably due to

large inter individual and small intra individual variation in absorption

and bio availability12. Eventhough psoralen appears to be distributed to

all cell organs, photochemical binding occurs only in the skin , eye and

blood71.

8-MOP is taken orally as a capsule in a dose of 0.6 to 0.8 mg/ kg

bodyweight, one to two hours before exposure to UVA radiation3.

In general, 0.4 mg /kg bodyweight is recommended because of

more predictable absorption, lower incidence of nausea and one hour

interval is more convenient for patient and cost saving70.

The liquid methoxalen formulation provides more rapid, higher

and more reproducible peak serum level than crystalline formulation18.

Tolbutamide displaces 8-MOP from its binding site and enhance

photosensitivity2.

19

MECHANISM OF PSORALEN’S ACTION

Photo activated psoralen is mostly confined to skin and eye, thus

PUVA represents a form of target related chemotherapy. The exact

mechanism by which photo sensitivity occurs following PUVA is not

precisely known. The absorption of psoralen maxima lie in 210- 310

nm. The action spectrum for oral PUVA is probably in the range of 320-

325 nm. In psoralen treated skin, on exposure to UVA rays, two

distinct reactions take place7.

TYPE 1 –ANOXIC REACTION

The site of cellular damage is primarily the DNA of the cell

nuclei by forming mono functional and bi functional adduct in the DNA

of melanocytes, there by increasing G2 phase of the cell cycle in which

Melanocyte Stimulating Hormone (MSH) receptors are more active33,18.

TYPE 2

It is oxygen dependent and forms free radicals .In this type,

reactive form of the psoralen in its triplet state and the site of these

reactions are DNA, chromatin, cell membrane of epidermis, dermal

endothelial cell, cytoplasmic constituents of melanocytes which cause

20

release of IL-1 and facilitate the binding of keratinocytes to more α

MSH receptors7.

Amelanotic melanocyte in hair follicle was discovered by

Staricco in 1959. The mechanism by which melanocytes repigment was

further elucidated by Orfonne et al and Cui et al63.

PUVA causes repigmentation by activation of the inactive

melanocytes in the middle and the lower part of hair follicle and hair

root sheath. Inactive melanocyte contains only structural melanosomal

protein but don’t contain enzymes required for melanogenesis63.

PUVA suppresses number of functional blood peripheral

lymphocytes, polymorphic mononuclear lymphocytes, macrophages and

T cell, diminished mitogen response showing beneficial effect within

immune reaction by reducing Langerhan cells 6 to 7 days after PUVA

and change in number and morphology of above cells and return to

normal by 14 days after stopping PUVA2.

El Mofty proposed the mechanism by which psoralen induces

pigmentation.

1) Release of inhibited tyrosinase enzyme31.

21

2) Induction of migration of active melanocytes from the

surrounding normal epidermis and hair follicle by inflammatory

mediators such as Leukotriene C4 (LTC4), Leukotriene D4

(LTD4) , TGF α, melanocyte growth stimulating factor which are

released by keratinocytes secondary to UV damage7.

3) Increased tolerance to UVR / solar exposure and thereby stronger

stimulation of melanocytes7.

4) Correction of abnormalities of structure of melanocyte in

vitiliginous skin7.

5) Reactivation of inactive melanocytes in vitiliginous patch7.

PUVA increases denova expression of SA beta galactosidase, a

marker of fibroblast senescence in vitro and vivo which result in 5 to 8

fold upregulation of matrix metaloproteinase I, III and result in

premature aging26.

UVA exposed kertinocytes express 2 factors (P-1, P-2),. with

molecular weight 20KDa, 1 KDa respectively. Its stimulates DNA

synthesis in human keratinocytes by expression of cytokines like IL6,

IL8, Granulocytes / macrophages colony stimulating factor11.

22

PUVA treatment may deplete vitiligo associated melanocytic

antigen (VAMA)68. PUVA inhibits ‘S’ phase of cell cycle57.

ULTRA -VIOLET RADIATION

Ultra violet radiation is a part of spectrum of electro magnetic

radiation. Wave length less than 290 nm are absorbed by ozone layer

which is about 25- 30 km above the earth’s surface. The wave length

less than 260 nm are absorbed by cellular protein and wave length of

280nm are absorbed by cellular nucleic acid , causing cell damage and

cell mutation45.

Absorbed by ozone Reaches earth’s surface

UVC UVB UVA

200 nm 290 nm 320 nm 400nm

23

CHARACTERISTICS OF UV AND VISIBLE LIGHT 35

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UVA 0 200-290 -- +++

+++ -- Epidermis

UVB 1.7 290-320 -- ++ ++ ++ Epidermis + Papillary dermis

UVC 6.3 320-400 + + + + Papillary + reticular dermis

Visible 9.2 400-800 + -- -- + Reticular dermis + subcutaneous Fat

Maximum UVL reaches the earth at noon because of the

transverse passage of rays. More UVL reaches the earth in summer50.

Solar radiation that reaches the earth is either reflected, transmitted or

attenuated by gas molecules and water droplets at 330 nm, by

stratospheric ozone absorption between 200 to 330 nm and by oxygen

below 200nm27.

UV rays are reflected by snow (85%), sand (25%), dribbling

water (5%), decreased by cloud 20-90%, 60% by every 50 cm traveled

through water27.

UVC is totally filtered by atmospheric ozone and is not present

in sunlight. It can be artificially produced by the use of filters. Artificial

24

source of UVC is cold quartz. They are inexpensive, do not need time to

warm up or cool off. UVC is mutagenic in vitro, effectively killing

micro organisms in the immediate vicinity. It is used for sterilizing

environment in the operating rooms. Desquamating effect of UVC have

been used to treat acne patients. UVC does not promote skin

pigmentation, but it does cause an immediate burning sensation and

desquamation 24 to 48 hours after treatment. It has the highest energy

part of the UV radiation38,27.

UVB (290-320nm)

It is referred to as sunburn spectrum because exposure to this

causes sunburn and delayed tanning. In addition, certain individuals

react abnormally to solar radiations such as urticarial papules, vesicles,

plaque etc33.

UVA (320-400nm)

It causes depletion of antigen presenting cell and induces

transient and less effective immune suppression. UVA rays can

penetrate the skin deeply upto subcutis and trigger the production of

melanin causing immediate tanning and premature ageing, stratum

corneum thickening and epidermal hyperplasia55. On earths surface the

25

ratio of UVA to UVB 20:127. UVA is strongest between 10 A.M. and 4

P.M. This is not absorbed by unstained glass and has the lowest energy

of UV radiation38. UVA increases skin temperature to cause pain at

42° C and immediate pigmentation between 6 and 20 j/sq. cm23. UVA is

sub-divided into UVA 1 (340-400nm) and UVA 2 (320-340nm).

Biologically speaking, UVA 2 is more effective than UVB27.

The psoralen photo chemotherapy action spectrum is UVA

portion of eletro magnetic spectrum.

26

PHOTOTHERAPY UNITS

PRINCIPLES OF PHOTOTHERAPY :

UV radiation is produced artificially by the passage of electric

current through a gas, usually vaporized mercury. The mercury atoms

become excited by the collision of electrons flowing between the lamp’s

electrodes. The excited electrons return to the particular electronic state

in the mercury atom and in doing so they release some of the energy that

they had absorbed in the form of optical radiation which is called as UV

rays45.

All bodies whose temperature is above absolute zero (Kelvin = -

273 °c) emit electro magnetic radiation. The higher the temperature, the

more intense becomes the radiation and the greater becomes the short

wavelength radiation components. With rising temperatures, the short

wavelength ranges increase more strongly, and the longer wavelength

ranges less strongly than the total radiation.

The Stefen- Boltzmann law states that the total electro magnetic

radiation of a body varies with the fourth power of the temperature. In

this case, the total radiation signifies the wavelength range between zero

and infinity.

27

TYPES OF PHOTOTHERAPY UNITS AVAILABLE:

1) Conventional incandescent lamps

2) Halogen incandescent lamps

3) Discharge lamps

4) Low pressure mercury vapour lamps

5) High pressure mercury vapour lamps

6) Metal vapour halogen lamps

7) Short arc mercury vapour lamps (maximum pressure lamps)

8) Xenon short arc lamps.

9) Fluorescent lamps

DISCHARGE LAMPS :

In this the radiation is generated when current flows through

gases or metal vapors. The non conductive gas to a conductive state is

done by means of high voltages which are briefly applied and are

generated by specially designed starters or ignition systems. There are

used for cosmetic and therapeutic applications and are intended to

generate UV and short wavelength IR radiations simultaneously. The

source for the UV radiation is a mercury high pressure arc tube. IR

radiation is generated by a tungsten coil .This coil also performs the

28

function of ballast resistance too. Discharge lamps are supplied in many

size and designs.

1) Low pressure mercury lamps

2) High pressure mercury lamps

3) Low pressure sodium lamps

4) High pressure sodium lamps

5) Metal vapour lamps

6) High pressure xenon lamps

7) High pressure krypton lamps

LOW PRESSURE FLUORESCENT LAMPS

Lamps emit radiation within UVA 350 and 370 nm.

PROPERTIES

Power levels, compact lamps 7-18 W

Power level, tubes 40-100 W

Lamp lengths, compact lamps 14 – 24 cm

Lamp lengths, tubes 60-180 cm

Supply voltage 125 – 230 V

Operations Using chokes and starters or using

electronic adapter systems. All systems

29

must be approved for the respective

type of lamp,

Brand Designation Light colors 78 and 79, Eversun Super,

TL / 10,12, TL/09, CLEO.

INFLUENCES THAT CAN CHANGE THE RADIATION OF

A LAMP:

Depending on the time, temperature, mechanical and electrical

adjustments, variations of the lamp emissions can result. Sometimes also

the bulb material will change without consequences in the visible range,

but it is possible that by this constructive variation, the UV radiation

will be changed. Some of these influences can ameliorate. For example,

by prolongation of the irradiation time or by better cooling40.

In this study, high pressure mercury vapour half body and hand

and foot lamps were used in the phototherapy units. These are compact

lamps. It contains mercury. This type of lamp is relatively economical as

a long service life of many thousands of hours and is used widely

nowadays in the treatment of psoriasis and vitiligo. The bulbs have 125

– 1000 watts power45.

The spectral emission from this type of units is from 254 nm -

366nm peak 352 nm and emit approximately 0.5 % of UVB. High

30

pressure mercury lamps are manufactured at the power level of 125

watt, with a so called black glass bulb which absorbs the visible lines

and transmits only the UVA line at 366nm40,25.

Regular broad band UVA lamps, which are manufactured for

PUVA therapy, serve as light sources for the photo chemotherapy for

vitiligo. These are either fluorescent lamp bulbs or metal halide lamps. If

metal halide lamps are use, a UVB filter is required to eliminate the

shorter wavelength portion of the emission spectrum.

DOSIMETRY:

The radiation energy from PUVA is converted into electrical

energy and readout by instrument called radiometer. It is made up of a

radiation filter, input optical and a detector where as that at specific

wavelength known as the spectral radiation is measured with the much

more complex spectroradiometer which includes a monochromator

instead of filter. The radiation dose is then calculated as the product of

measured irradiance and the exposure in time (Sec). Four commonly

used are photomultiplier tube, vacuum photo tube, solid state photo

diode, thermopile. Photo multiplier tube are very sensitive but fragile.

Solid state photodiodes are more robust, small and suitable for rapid

portable radiometry (eg) phototherapy equipments. Thermopile are

31

small robust, have flat spectral responses are best for the quick accurate

measurements of monochoromatic irradiance or of serial broad band

irradiance of fixed spectral content.

The dosimetry of photochemotherapy of vitiligo needs always to

be done with special care because over exposure may result in serious

adverse reactions. There are no parameters that allow a reliable

prognosis for an individual patient. It has been demonstrated that after

PUVA treatment, the majority of the patients retain PUVA induced

repigmentation for many years. Neither the pathogenesis of vitiligo nor

the mechanisms of regimentations by photo therapies are completely

understood3,18.

UV radiation is present in sunlight also. In vitiligo, 8-MOP is

conjugated with sunlight exposure is called as PUVASOL therapy2.

The exposure done is done in outdoor between 10 am to 3 pm,

two or three times per week .It is never done on consecutive days. Sun

exposure is initially limited to five or ten minutes for Type 1 / 2 or 3 and

greater skin types respectively, increasing by five minutes with each

exposure. At that time a gradual increase is allowed based on redness

and tenderness for upto two hours45. The disadvantage of therapy is

difficulty in quantifying UV rays and total amount of UV rays may also

32

vary according to the season, time of the day, latitude and condition of

atmosphere7.

The irradiation of light is measured in milliwatt/cm2 with the

help of an approximately calibrated radiometer .The dose of UVA

irradiation is employed to calculate the exposure time for the desired

dose in Joules.

Energy (joule) = Power(watt) Χ exposure time (second)

Fluence (J/cm2 = irradiance (W/cm2) Χ exposure time (sec)

Prescribed UVA dose (J/m2) Exposure time (mts) = 0.06 irradiance (mw/cm2)

VARIATION OF IRRADIANCE.

Irradiance (power density) varies directly with power source and

inversely with surface area (therefore inversely with the square of

distance from the power source.

11 Χ D12= 12 Χ D22 ( I= irradiance; D= distance)

D12 / T1 = D22 /T2 ( T= exposure time)

33

Grading of erythema

E0 - No erythema

E1 - Minimally perceptible erythema (faint pink)

E2 - Marked erythema (red)

E3 - Fiery red erythema with oedema

E4 - Fiery red erythema with oedema and blistering

In pigmented patient, sometimes erythema and oedema may not

be seen. Instead of these, patient may complain of hotness and tightness

of skin.

Erythema is a limiting factor in phototherapy – E1 should not be

exceeded. The onset of UVA – induced erythema has a delayed onset of

48 hours after exposure.

MPD (Minimal phototoxic dose ) = The dose of PUVA required

to produce a E1 reaction 48 hours after exposure.

MED (Minimal erythemogenic dose) = The dose of UVB

required to produce a E1 reaction 24 hours after exposure13.

34

MPD is can be accomplished by using a template with six to

eight 2 x 2 cm squares cut out and applied to a sun protected area, such

as the buttocks. After the rest of the patient’s skin is shielded with

appropriate UV opaque covering, graduated doses of UV light can be

delivered to the test site by sequentially blocking the template openings

with opaque material at increments designed to produce an array of UV

light exposure lightly less or greater than the expected MED or minimal

phototoxic dose based on the patient history. This is done after

administering the photosensitizer (1½ - 2 hrs) after oral psoralen and 1

hour after topical psoralen5.

Usually the first dose range from 0.5 to 5 J /cm2. Minimum

Phototoxic. Dose (MPD) thus determined indicates the first therapeutic

UVA dose for the follow up and adjustment of the dose, determination

of photosensitivity, pigment index (PDI) become necessary. This is done

by reading the erythema and pigmentary reaction after 72 hours and 120

hours in the first test field exposed for MPD determination. The PDI

serves to assess the patient’s capacity to develop the tolerance to photo

toxic reaction by pigmentary reaction of the skin18,3.

Perifollicular pigmentary dots were the first to appear followed

by the hyperpigmentation of the border. Dots of pigmentation usually

35

develop after 20 to 30 exposures. , 50 exposures on trunk and proximal

extremities, and near total repigmentation usually requires 50 to 300

exposures8.

VARIOUS SCALES IN PUVA ASSESSMENT

1) Based on RULE OF NINE39

2) Assessment scale proposed by Hossain17

Parameter -- + ++ +++ ++++ Change in colour

No change Yellowish tint Slight contrast between lesion color and surrounding skin colour

No contrast between lesion color and surrounding skin colour

100% remission in all treated lesions

Change in size NO change Up to 5mm reduction in diameter

Up to 10mm reduction in diameter

More than 10mm reduction in diameter

Folliculocentric repigmentation

No repigmentation.

Upto 5mm perifollicular repigmentation

Upto 10mm perifollicular repigmentation

More than 10mm perifollicular repigmentation.

3) Vitiligo Area Severity Index69

The percentage of vitiligo involvement is calculated in terms of

hand units. One hand unit (which encompasses the palm plus the volar

surface of all digits) is approximately equivalent to 1% of the total body

surface area. The degree of pigmentation is estimated to the nearest of

one of the following percentages : 100% - complete depigmentation, no

pigment is present; 90% - specks of pigment present; 75%- depigmented

area exceeds the pigmented area; 50%- pigmented and depigmented area

36

are equal; 25% - pigmented area exceed depigmented area; and 10% -

only specks of depigmentation present.

The VASI for each body region is determined by the product of

the area of vitiligo in hand units and the extent of depigmentation within

each hand unit measured patch. Total body VASI =Σ all body sites

(Hand Units0 x (Residual depigmentation) Vitiligo disease activity score

(VIDA). The VIDA is a six-point scale for assessing vitiligo activity.

Scoring is based on the individual’s own opinion of the present disease

activity over time. Active vitiligo involves either expansion of existing

lesions or appearance of new lesions. Grading is as follows : VIDA

score +4- activity of 6 weeks or less duration : +3 – activity of 6 weeks

to 3 months; +2- activity of 3-6 months ; +1- activity of 6-12 months; 0

– stable for 1 year or more; and – 1- stable with spontaneous

repigmentation since 1 year or more. A low VIA score indicates less

activity.

ADVANTAGE OF SYSTEMIC PUVA OVER TOPICAL PUVA:-

• Oral PUVA treatment is less laborious and time consuming than

topical PUVA.

• Erythema and blister formation is less commonly seen than topical

PUVA.

37

• Improvement is more regular than with topical PUVA39.

PUVA and HIV Infection

Systemic PUVA can be safely used for the treatment of HIV

positive infected patients and is a practical regimen with little or no risk

of disease transmission and well accepted by the patients. But for more

advanced HIV infection systemic PUVA is not recommended47.

DISADVANTAGES :-

Systemic side effects such as nausea, vomiting, carcinogenic

effects, and cataracts are more common with oral PUVA21.

PUVA has been shown to effect immune reactions. PUVA also

has possible effects on the function of polymorpho nuclear leucocytes,

formation of antibodies, immune complexes and induction of auto

immune diseases. PUVA treatment should be closely monitered for

induction of LE47.

INDICATION FOR PUVA IN VITILIGO

1. Generalized vitiligo ( more than 20 % of body surface area)46

2. Segmental vitiligo

3. Acral vitiligo14

38

4. Acro facial vitiligo

5. No response to topical medication3.

CONTRAINDICATION FOR PUVA IN VITILIGO

ABSOLUTE:-

1) Bloom’s syndrome

2) Trichothiodystrophy.

3) Previous melanoma

4) Xeroderma pigmentosum.

5) Systemic lupus erythematosus.

6) Cockayne’s syndrome

7) Gorlin′s syndrome47

RELATIVE CONTRAINDICATIONS:-47

♦Age <10 years •Age < 16 years ♦Concurrent Malignant disease •Cataract ♦Concurrent Immuno Suppression •Bullous Pemphigoid, pemphigus

vulgaris ♦Pregnancy , Lactation • Significant Hepatic dysfunction ♦Porphyria Previous internal malignancy ♦Previous Exposure to arsenic and X rays

MINOR MAJOR

39

SIDE EFFECTS OF PUVA14,15,70,71,

Acute clinical side effect :-

These are due to the drugs (photo toxic reactions)

1) Erythema

2) Pruritis

3) Koebnors Phenomenon

4) Severe pain in the skin

5) Drug eruptions

6) Nausea , headaches, bronchial hypersensitivity

7) Phyto photo dermatitis

8) Ankle edema

9) Blister.

DUE TO METHOXSALEN ALONE :-

Gastro intestinal disturbance, CNS disturbance like headache,

dizziness, light headedness, depression, insomnia, feeling of detachment

from the environment. Bronchoconstriction, hepatic toxicity and drug

fever71.

CHRONIC SIDE EFFECTS :-

• Hyper pigmentation and xerosis14

• Premature ageing and wrinkling54

40

• Hyper trichosis2

• Nail changes – pigmentation, subungual hemorrhage43.

• Precancerous skin conditions – actinic keratosis15, seborrhoeic

keratosis , Keratoacanthoma , Bowen’s disease2.

• Cutaneous malignancy like squamous cell carcinoma,

melanoma36,48,65.

• Aggravation of underlying skin disease like seborrhoeic dermatitis,

acne, bullous pemphigoid, lupus erythematosis, cataract,

disseminated superficial actinic porokeratosis, hepatotoxicity,

nephrotic syndrome and exacerbation of gouty arthritis1,2.

COMBINATION OF TREATMENT UTILIZING PUVA :-

PUVA PLUS TOPICAL THERAPY

PUVA + Calcipotriene70

PUVA + Steroids

PUVA + Minoxidil

PUVA + Anapsos

PUVA +Autologous split skin graft3 .

PUVA treatment can be divided into two phases ,

1. The clearing phase.

2. Maintenance phase.

41

The clearing phase begins with the commencement of therapy

and ends with clearing of atleast 95 % of treatable lesions.

The maintenance phase on the other hand is subject to

considerable variations in frequency and duration as well as dose

adjustment.

The determination of the starting UVA dose has been classically

dependant on the establishment of skin type in the United States and

whereas in Europe, it is based on minimal phototoxic dose (MPD) and

in some instances the photopigmentary index of each individual (PPI)

.The Austrians use MPD or the combination of MPD and

photoPigementary index18.

FITZPATRICK SKIN TYPE21

Code Description

I Always burn , never tans

II Always burn , tans minimally

III Burn moderately, tan gradually

and uniformly (light brown)

IV Burn minimally , always tan well

(moderate brown)

V Rarely burns , tans profusely (dark

brown)

VI Never burns , deeply pigmented

(black)

42

UVA Exposure according to Skin Type

Recommended Skin Type

Initial Maintenace Dose (J/cm2)

Increment dose (J/cm2)

1 4-6 0.5-1 2.5-5 2 6-8 1-2 0.5 3 8-10 1.5-3 0.5-1 4 10-12 2-4 1 5 12-14 2.5-5 1 6 14-16 3-6 1-1.5

The dose of UVA is increased from 0.5 –1 J /cm2 depending on

the skin type or an individual response. The treatment is given usually

two to three times weekly atleast 48 hours apart to permit evaluation of

any erythema resulting from preceding treatment. If painful eythema and

blister persist and wide spread, the treatment should be restarted, once

the lesion completely subsides and restarted at minimal dose lower than

the previous treatment dose. If still erythema occurs, artificial UVA dose

or sunlight exposure should be withheld constantly. Marked erythema

due to photo toxicity should be avoided since subsequent koebnerization

may cause reversal of repigmentation .

During the UVA irradiation, protective eye goggles should be

worn. Clothing should not be worn and sun screen should not be used

before UVL exposure. During UVL treatment, protection of face with a

pillow case and male genitals with an athletic support is often advised.

The patient should be advised to avoid exposure to sunlight for 8 hours

43

after taking UV light treatment. If exposure is unavoidable skin should

be protected by clothing, hat, and sunscreens that block UVA18,24.

Maintenance schedule

The final clearance dose of irradiation is held constant and the

frequency of treatment is gradually reduced as follows.

Four treatments at weekly interval

Then,

Four treatments every other week

Then,

Four treatments every third week

Then,

Four treatments every fourth week

Then ,

Stop treatment or continue monthly treatment70

Special glasses should be worn to protect the eyes even when

indoors; window glasses may not shield UVA light. Hence protective

eyewear must be worn, lubricating lotion / Emollient lotions can be used

for dry skin following the treatment18.

If regimentation is not seen even after 20 – 30 treatments, the

dose of 8 MOP can be increased. If still desired results are not achieved

44

after another 20 – 30 treatments, the treatment is to be viewed as a

failure13.

If treatment is interrupted before an area gets completely

repigmented, the area once again becomes depigmented within a short

time . Psoralen therapy also increase the tolerance of affected skin to

sunlight possibly through thickening of the stratum corneum3.

TOPICAL PUVA.

If vitiligo macule is less than 6 cm2 in size, 0.1 % of psoralen

lotion can be applied weekly followed by one and half to two hours later

exposed to sunlight for 30 – 60 seconds. And duration can be increased

by 30 seconds per sitting until light erythema occurs on the day

following the exposure. Alternatively the area is exposed to black light

source at a distance of 4 cm for 4-5 minutes. Initial exposure dose is 0.5

J/cm2, with increment of 0.25 –0.7 J/cm2 in the subsequent treatment

until a light pink colour is obtained. After treatment exposure, the area

should be washed with soap and water and covered with a clothing or

with a sunscreen3,18.

Other modalities available are :-

• Bath PUVA and Bath suit PUVA. The advantage of this method is

systemic toxicity can be avoided18.

• 5- MOP ( 5 Methoxy Psoralen)

45

A dose of 1.2 –1.8 mg /Kg body weight is said to be as effective as

8- MOP when given at a higher dose or a high dose of UVA radiation .

Side effects are less and decreased phototoxicity due to decreased

concentration in the epidermis2,34.

• Trimethyl Psoralen (4, 5, 8 MOP) is often used topically and orally21.

• 3 Carbethoxy Psoralen (3 CP) may be therapeutically effective but

less phototoxic than 8 MOP in humans18.

46

METHODS AND MATERIALS

Forty one patients of either sex with stable generalized type,

acral, acrofacial type of vitiligo with > 20 % of body surface area

involvement were enrolled for the study after obtaining the informed

consent. History included the following:

1. Age of onset of depigmentation

2. Course of the disease – stability, rate of progression

3. Potential precipitating events including emotional stress,

cutaneous trauma

4. Any history of photosensitivity

5. Ocular or auditory dysfunction

6. Family history of vitiligo and early graying of hair

7. Personal or family history of autoimmune diseases

All patients were examined under good light. Importance for

the distribution, number of lesions, colour of lesions, the affected sites in

the skin,approximate surface area of depigmentation, pattern of vitiligo

and mucosal involvement were taken into account. Any presence of

leukotrichia in the patch were noted.

Any associated autoimmune disorders if present were noted .

Laboratory investigations like routine blood examination ( Hb, TC, DC,

ESR), urine analysis, liver function tests, thyroid profile were done.

47

Blood group, peripheral smears, blood sugar, serum creatinine were also

done .

INDICATIONS OF PUVA –INCLUSION CRITERIA

1) Generalized stable vitiligo

2) Acro facial vitiligo

3) Acral vitiligo

4) Patient who has given consent for clinical photo and treatment

EXCLUSION CRITERIA

1. Patient not willing to give written consent

2. Patient below 12 years and above 60 years

3. History of photo sensitivity and photo sensitive skin disorders

4. Pregnancy and lactation

5. Concurrent immuno suppressive and premalignant skin disease

6. Significant hepatic and renal dysfunction

Audiograms were done to rule out any sensory neural deafness.

Fundoscopy was done to rule out cataract and retinal pathology .Clinical

photographs were taken for all the patients before and after exposure to

PUVA therapy. This study was randomized single blinded age and sex

matched.

In each case initial lesions on both sides of the body were

assessed with the Rule of Nine. 8 -MOP tablets were given according

48

to the weight of the patient .After one and half to two hours the patients

were subjected to UVA exposure artificial phototherapy chamber

starting with a dose of 4 J /m2 over whole body.

An increase of dosage by 0.5J/cm2 was done provided there was

no generalized erythema or other side effects. Comparative assessment

of index lesions was done on each side in each case before starting

treatment and after every five exposure to UVA treatment for a period of

8 – 10 months..

METHODOLOGY

8 MOP tablets are given in the following doses (which is equal to

0.4 – 0.6mg./ kg body wt.)

Patient’s Weight (Kg) Dose in Mg. (1 tab – 10 mg)70

> 30 10 30-60 20 65-90 30 > 90 40

Drugs was taken in the empty stomach because of its absorption

was enhanced. If patient complained of nausea the tablets were taken

after a small meal. Subsequently after 1 ½ -2 Hrs, the patient’s whole

body was irradiated with UVA by an appropriate irradiation system. The

49

starting dose (Joule) was determined by Fitzpatrick skin typing. As the

Indians belong to Fitzpatrick’s Skin typing V, started at 4J/Sq.cm70.

Repeated exposure for 2 times/week was done to clear PUVA

responsive disease. Increment dose of 0.5 joules/sq.cm/1-2week during

each exposure was based on the patient’s response14.

During treatment the eyes were protected by wearing UV –

blocking goggles. An occasional exception was made in patients with

recalcitrant disease of the eyelids or periorbital skin, and at the

physician’s discretion40.

Before and after treatment with photochemotherapy, a) Patients

were advised to wear UVA – blocking glasses, whenever using sunlight

for illumination, from the time of exposure to psoralen until sunset that

day. In addition, patients were encouraged to wear UV – blocking

glasses when exposed to sunlight on the following day.

Patients were advised to should avoid unnecessary exposure to

sunlight on days they, receive treatment and were discouraged from

deliberate exposure to sunlight on nontreatment days. Patients were

encouraged to use sunscreen on exposed areas.

When trace of erythema was seen after 72 hrs, dose was not

increased and patients were treated with previous exposure time if side

50

effects were noted. When more than 95% clearance was obtained, the

last dosage was maintained and maintenance schedule was given. The

patients were assessed every fortnightly and values tabulated.

51

RESULTS

TABLE 1

OVERALL RESPONSE RATE

Data Mean SD Minimum Maximum

Age 41.27 11.45 18 60

No .of patch 27.73 8.58 15 50

No. of month 94.07 66.62 12 240

Extent of lesion 31.05 10.27 15 60

% of area involved 34.03 11.02 15 60

No.of sitting 57.67 30.67 5 100

Last visit 19.17 7 10 35

TABLE 2

TYPE OF VITILIGO

Type Total patient Percentage

Generalized 20 66.7 %

Acral 5 16.6%

Acro facial 5 16.6%

52

TABLE 3

AGE RESPONSE TO PUVA

Generalised type-Vitiligo

Vulgaris

Acral Acro Facial Age (yrs)

M F Response M F % M F %

10-20 -- 1 75 -- -- -- 1 -- 58

21-30 2 -- 63.5 2 1 43.6 -- 1 11

31-40 1 5 44 -- 1 50 -- -- --

41-50 3 3 36.7 -- -- -- 3 -- 42.6

51-60 4 1 57.45 1 -- 25 -- -- --

Overall response Vitiligo Vulgaris Acral Acrofacial

Female 50.7 % 50.00 % 11.1 %

Male 60.6 % 33.33 % 46.5 %

TABLE 4

ACUTE SIDE EFFECTS

a) Generalized type of Vitiligo

Symptoms No. of Patients (20)

%

Pruritus 8 26.6 Erythema 10 33.3 Bulla 2 6.66 Xerosis 7 23.33

53

b) Acral

Symptoms No. of Patients (5) %

Pruritus 1 3.3

Erythema 1 3.3

Bulla 0 -

Xerosis 1 3.3

c) Acrofacial

Symptoms No. of Patients (5) %

Pruritus 1 3.3

Erythemia 1 3.3

Bulla 1 3.3

Xerosis 1 3.3

TABLE 5

EXACERBATION FACTORS IN RELATION TO PUVA

Mild Moderate Good Excellent

Normal (24) 7 6 4 7

Exacerbation (6) 1 0 1 4

X2 = 3.6 p = 0.31 NIL SIGNIFICANT

54

TABLE 6

RELATION OF PHYSICAL AND CHEMICAL INJURY TO PUVA


Normal 8 4 4 11 INJURY 0 2 1 0


Causes of early discontinuation of PUVA in this study :

1) Long Distance 4

2) Lack of Compliance 3

3) Fear of side effects 2

4) Associated with DM and hypertension 2

Total 11

TABLE - 7

FAMILY HISTORY AND PUVA RESPONSE


Nil 3 5 3 7

Consanguinous marriage 2 0 1 2

Family members 3 1 1 2


55

TABLE – 8

OVERALL RESPONSE IN VARIOUS TYPES OF VITILIGO

Type Mild (<25 %)

Moderate(25-50

%)

Good (50- 75 %)

Excellent (> 75 %)

Generalized (20) 2 6 9 3

Acral (5) 1 2 2 --

Acrofacial (5) 1 3 1 --

TABLE – 9

PAIRED SAMPLES STATISTICS

N Mean SD Paired t-test

Initially involved 30 34.03 11.022 Last visit 30 19.17 6.998

t = 6.99 p = 0.001

( P < 0.05)

AGE RESPONSE IN RELATION TO PUVA

age

70605040302010

DIF

FER

50

40

30

20

10

0

-10

Nil Significant

56

DISCUSSION

Vitligo is a disease of unknown aetiology. Though it is not a life

threatening disease and does not require treatment, it causes cosmetic

disfigurement, emotional stress and social stigma. Therapeutic

approaches are directed to reverse the progressive loss of pigment

producing epidermal melanocytes and to reconstitute the normal skin

colour. Upto 20% patients with vitiligo experience transient

repigmentation in some skin area upon exposure to sunlight. However

photochemotherapy can induce permanent cosmetically acceptable

result9.

Aim of our study is to evaluate efficacy of PUVA treatment in

South Indian vitiligo patients by this prospective study. Forty one

patients were enrolled for this study. Out of which thirty patients

regularly took PUVA therapy. (<25% of their scheduled PUVA therapy)

The age of these patients ranged from 18 to 60 yrs. (mean age

41.72+/- 11.44)

57

Sixteen male patients and fourteen female patients were taken up for this

study giving male to female ratio of 1.2:1. Family history of vitiligo was

found in seven patients (23.33%) of which two were acral type (1 acral,

1 acrofacial type) and five were generalized type.

The types of vitiligo taken in our study were generalized (20

patients, 66.7%) , acral in five patients (16.6%) acrofacial in 5 patients

(16.6%). Duration of the disease ranged from 12 months to 240 months

(mean 94.07+/- 66.62). The percentage of the area of vitiligenous

patches extended from 15% to 60% giving a mean of 34.03% +/-

11.02%.

The cumulative doses ranged from 20 J/cm2 to 440 J /cm 2

with a mean of 230.4 J/cm2. Number of sessions to initiate

repigmentation ranged from 6 to 15 sessions (8.45%) in case of

generalized type and in case of acral and acrofacial type 8 to 18

sessions (11%) which is comparable to the study done by James

E.Fluton where clinical repigmentation started after two to ten

treatments in generalized type of vitiligo30.

Onset of repigmentation was found to be earlier in young males

in generalized type and in young females in case of acral type. In

acrofacial type it was seen in young male patients59.

58

The maintenance doses ranged from 6 to 12 J/cm2 giving a mean

of 6.77J/cm2. When the maximum cumulative doses of 440J/cm2 (100

exposures) was given, good response was noticed among the younger

age groups in all three types of vitiligo. (acral, acrofacial and

generalized types)59.

On following up the patients fort-nightly, initial erythema was

noticed in 40% of patients followed by perifollicular repigmentation,

which is consistent with the study stating that initial erythema was

necessary for repigmentation8. (Fig. 1 & 2)

All the patients were assessed based on the “Rule of Nine”. In our

study we noticed along with perifollicular pigmentation

hyperpigmentation at the border of the patches as reported earlier24,2.

In generalized type, excellent response was seen in 3 patients

(15%), good response in 9 patients (45%), moderate response in 6

patients (30%) and mild response in 2 patients (20%). (Fig.3, 4,5,6,7,8,9

& 10)

In acral type good response was seen in two patients (40%).,

moderate response was seen in two patients (40%) and mild response in

1 patient(20%). (Fig. 11,12,13 & 14).

59

In acrofacial type good response was seen in 1 patient (20%) ,

moderate response in 3 patients (60%) and mild response in 1 patient

(20%)

Our study showed that analysis of factors affecting the response

rate such as age, koebnerisation, exacerbating factors like sunlight,

emotion, stress, infection etc., do not affect response rate which also

correlate the previous studies68.

In our study , good response was found in the patients with blood

group “O” positive but Srivastava and Shukla observed more

predilection for the blood group “B” and “AB”22.

Acute side effects noticed in our study were erythema, pruritus,

xerosis and bulla. In generalized type, pruritus was seen in eight

patients (26.6%), erythema in 10 patients (33.3%) bullae in 2 patients

(6.66%) and xerosis in 7 patients (23.33%). In acral type pruritus ,

xerosis and erythema was observed in one patient each (3.3%). In

acrofacial type of vitiligo pruritus, xerosis, erythema and bullae were

noticed in 1 patient each (3.3%).

60

The mild erythema (grade 1)13 was observed after 12 to 24 hrs.

and subsided by 42 to 72 hrs. is compatible with previous studies,

grading as per previous reference2.

We found that none of the patients enrolled in the study

developed pain and painful erythema over the vitiliginous patches after

80 to 100 sessions. Erythema was treated with cool compresses,

emollient lotions and shielding of affected area. Pruritus was treated

with oral anti histamine,emollient and topical steroids . Bulla was

noticed in two patients in case of generalized type of vitiligo at

6J/cm2.The treatment was restarted after the lesions had completely

healed at a dose lower than the previous treatment dose (2J/cm2). After

10 exposures of PUVA, 2 patients again developed blister and therefore

were discontinued. Bulla was observed in 1 patient in acrofacial type at

10J/cm2. Hence, the patient was placed in the maintenance dose of

8J/Sq.cm13.

61

Chronic side effects like hypertrichosis was seen in one patient of

generalized type of vitiligo over the patch and other long term side

effects like cataract, premature aging and PUVA lentigenes were not

observed in study67. Similar to the previous study done in the UVA

response in the vitiligo in Saudi patients.

At the end of our study (8-10 months) bio chemical parameters

were again repeated. None of the patients showed any significant

changes in their blood parameters.

In our study, trunk, face, arms, legs showed near complete

repigmentation, while distal dorsal surface of hands, feet, tips of fingers,

palms and soles , nipples bony prominences rarely showed complete

repigmentation, which is consistent with the previous study of PUVA in

Saudi vitiligo patients4. The patches with leukotrichia showed poor

repigmentation21.

62

CONCLUSION

In our study, the only factor to affect the overall response rate with

the statistical significance (P.001) was the surface area of

involvement was directly proportional to the total session to induce

pigmentation (p value <0.05).

Our data showed that the following factors like the age of the patient,

family History of vitiligo, Koebnerization, precipitating factors and

the age at the onset of disease have no influence on repigmentaion,

though the onset of repigmentation was found to be earlier in

younger patients.

Hairy areas (Face, Legs, arms, trunk) were more sensitive to therapy

while non hairy areas (mucosa, finger tips, toe tips, palms & soles)

were less sensitive to therapy.

Generalized type was the best type to respond very well. Acral and

acrofacial types were resistant to therapy.

Good response was noticed in young patients with blood group ‘O’

positive individuals.

In our study, patients with longer duration of disease showed slower

response to therapy.

We conclude, that Puva is effective, safe and cosmetically acceptable

therapy for vitiligo.

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PROFORMA

Name : Age :

Address : Sex :

Occupation :

1) Complaints : No. of patches, Sites

2) Durations :

3) Activity : Progressive, Static, Spontaneous repigmentation

4) Factors exacerbating - seasonal, emotional, infections, drugs, sunlight

5) History of Injury - Physical - present / absence

Chemical - present / absence

6) Associated Visual disturbance / Deafness

7) Family History - Consangunity in parents Other family members affected with Vitiligo Associated diseases in the family

8) Treatment History - Ayurvedic Homeopathic Allopathic No treatment

9) Associated autoimmune diseases :

1) Hypothyroidisrn 5) Rheumatoid arthritis

2) Hyper thyroidism 6} Alopecia areata

3) Pernicious anaemia 7) Addisons disease

4) Diabetic mollitus 0) Atopic Dormntilis

10) Examination (sites; Sun exposed Covered area mucosa - oral, genital, scalp palm / sole leucotrichia Loebner's phenomenon

11)

Local Focal mucosal segmental

Whole body / Hand + Foot

Generalised vitiligo vulgaris Acrofacial universalis

15) General Examination Anaemia Jaundice cyanosis clubbing Lymphadenopathy

12) Extent (%)

type of vitiligo

14) PUVA

16) Systemic Examination : CVS :

RS :

Abdomen :

17) Particulars :

Date of Visit

Weight

Height

Pulse Rate

Blood Pressure

16) Investigations :

1) Hb

2) TC

3) DC

4) ESR

5) Peripheral Smear

6) Blood grouping

7) Blood Sugar

8) Blood Urea

9) Serum Creatinine

10) Liver Functin Test

SGOT

SGPT

Alkaline phosphatase

Total bilirubin

19) Psoralen Dose : Oral / topical application

20)

Date of Visit

Dose f UVA

Side effects

New Lesions

Old Lesions Repigmentation

Stat Worsen Better

ABBREVIATIONS

TGF - Transfer Growth Factor

IR - Infrared Radiation

IL6 - Interleukin

UVA - Ultraviolet A Rays

UVB - Ultraviolet B Rays

UVC - Ultraviolet C Rays

DM - Diabetes Mellitus

CLA - Cutaneous Lymphocytic Antigen

PUVA CHAMBER

BEFORE ILLUMINATION

AFTER ILLUMINATION

HAND AND FOOT PUVA

GENERALISED TYPE OF VITILIGO VULGARIS

BEFORE PUVA (Fig. 3)

AFTER PUVA (Fig. 4)



AFTER PUVA (Fig. 8)



AFTER PUVA (Fig. 6)



AFTER PUVA (Fig. 10)



AFTER PUVA (Fig. 2)

ACRAL TYPE OF VITILIGO

BEFORE TREATMENT (Fig. 11)

AFTER TREATMENT (Fig. 12)

BLISTER

COMPLICATION

ERYTHEMA

RUPTURE BULLA

EROSION AND ULCER

ACRAL TYPE OF VITILIGO


AFTER PUVA (Fig. 14)

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